The present invention is concerned with a combination of an aromatase-inhibitor and an antiandrogen for use in the prophylaxis and/or treatment by therapy of benign prostatic hyperplasia (BPH), and with pharmaceutical preparations and packs or kits suitable for such use.
Benign prostatic hyperplasia involves a benign enlargement of the prostate gland which starts in the so-called "inner" prostate gland. Discomfort can be attributed primarily to the obstructions of the urethra that occur. Voiding of the bladder is impeded and residual urine is retained. Without surgical treatment uremia may occur.
Up to now it has been almost impossible to treat this disorder, very frequent in older men, using medicaments. The phyto-preparations used for this purpose, such as, for example, .beta.-sitosterin, mixtures of various plant extracts and combinations of plant extracts with the neurotropic spasmolysant azoniaspirochloride have proved ineffective in a one year study. Although the patients under therapy experienced an improvement in the micturition symptom, a regression of the hyperplastic prostate gland was not achieved.
Hormones, too, find application in the treatment of prostatic hyperplasia. Of these substances the depot gestagen gestonorone caproate is worthy of special mention. Compared with the phyto-preparations, an improved action is obtained with gestonorone caproate. The prolonged duration of micturition before the treatment is distinctly shortened and the maximum flow value (flow of urine per unit of time) is improved. A distinct reduction in the size of the adenoma cannot, however, be detected in this case either.
Prostatic hyperplasia involves a benign enlargement of the prostate gland, in which both the interstice (stroma) and the epithelium participate to a varying degree. Hormonal effects have been strongly implicated in the etiology. Heretofore, it has been presumed that abnormal levels of androgens contribute to the enlargement. As a result, antiandrogenic therapy has been suggested by many. See, e.g., U.S. Pat. No. 3,423,507 (e.g., administration of the antiandrogen, cyproterone acetate, i.e., 1.alpha., 2.alpha.-methylene-6-chloro-17.alpha.-acetoxy-6-dehydroprogesterone), U.S. Pat. No. 4,055,641, etc. More recently, evidence has been gathered which suggests that, inter alia, a shifting of the estrogen/androgen ratio in favor of estrogen may be regarded as a cause of BPH. That is, suggestions have been made that an increase in the estrogen level can contribute to the enlargement of the prostate. Thus, the state of the art establishes an expectation that an increase in the estrogen level and/or an increase in the androgen level will contribute toward BPH, while a shifting of the estrogen/androgen ratio in favor of the amount of estrogen, inter alia, may also be regarded as a cause of BPH. Moreover, various investigations have shown that in older men the concentrations of serum testosterone fall off; at the same time the proportion of SHBG (sex hormone binding globulin, specific transport protein for steroids) increases, so that the biological availability of androgens decreases still further.
Thus, the literature establishes an expectation of a benign enlargement of the prostate due to an increase in the estrogen level alone, an increase in the androgen level alone, or an increase in the estrogen/androgen ratio.
For example, in U.S. Pat. No. 4,310,523 it is proposed that a combination of an antiestrogen and an antiandrogen is effective for the prophylaxis and/or therapy of benign prostatic hyperplasia. This reference attests to the fact that both the effects of estrogen and the effects of androgen are important since medicaments directed against each are necessary. The method of this patent is disadvantageous since the physiological effect of the antiestrogens is highly dosage specific; for example, at relatively high doses, antiestrogens will act agonistically, i.e., as estrogens. Similarly, the mentioned treatment of U.S. Pat. No. 3,423,507 using gestagenically and antiandrogenically active esters such as cryproterone esters, is disadvantageous since only a partial regression of the hyperplasia is effected, no doubt due to the failure to treat the estrogenic factors. All of the evidence shows that both factors must be treated.
A further suggestion of the role of increased estrogen levels in the development of BPH is contained in the disclosures of H. U. Schweikert (1979): "Conversion of androstenedione to estrone in human fibroblasts cultured from prostate, genital and nongenital skin." Horm. Metab. Res. 11, 635-640; Schweikert, H. U., Hein, H. J. and F. H. Schroeder: "Androgen metabolism in fibroblasts from human benign prostatic hyperplasia, prostatic carcinoma and nongenital skin" in `Steroid receptors, metabolism and prostatic cancer.` Editors: F. H. Schroeder and H. J. de Voogt, pages 126-133, Excerpta Medica (1980), International Congress Series No. 494, Amsterdam, Oxford, Princeton. These references report the results of studies showing that fibroblast cultures from human prostatic hyperplasia tissue are able to aromatize testosterone to form the corresponding estrogens more strongly than fibroblast cultures originating from healthy prostate tissue. The phenomenon of aromatization of androgens to form estrogens in the prostate gland is consistent with previous findings that estrogens present in men originate predominantly from peripheral aromatization of androgenic hormones and not from testicular biosynthesis, as contained in the disclosures of H. U. Schweikert: "Befunde zum Androgenmetabolismus" in `Androgenisierungserscheinungen bei der Frau,` editors: J. Hammerstein, U. Lachnit-Fixson, F. Neumann and G. Plewig, pages 42-50, Excerpta Medica (1979), Amsterdam, Oxford, Princeton; MacDonald, P. C., Rombaut, R. P. and P. K. Siiteri (1967): "Plasma precursors of estrogen. I. Extent of conversion of plasma .DELTA..sup.4 -androstenedione to estrone in normal males and nonpregnant normal, castrate and adrenalectomized females." J. Clin. Endocrinol. Metab. 27, 1103-1111; Weinstein, R. L., Kelch, R. P., Jenner, M. R., Kaplan, S. L. and M. M. Grumbach (1974): "Secretion of unconjugated androgens and estrogens by the normal and abnormal testis before and after human chorionic gonadotropin." J. Clin. Invest. 53, 1-6.
It can thus be seen that BPH is a condition considered by the prior art to be caused both by increased estrogen levels and increased androgen levels or an increase in the estrogen/androgen ratio. The precise etiology has not yet been elucidated. Because of the existence of both estrogenic and androgenic factors, proposed hormonal treatments have been less than satisfactory and have not been predictable with any degree of reliability. For example, if one were to consider the possibility of inhibiting the aromitization of androgens into estrogens using any of the known aromatase-inhibitors, it could not be expected that such treatment would be successful. As indicated, an increase in the amount of androgens has been established as one cause of BPH. Since an aromatase-inhibitor would decrease the amount of estrogen, but at the same time would increase the relative amount of androgen, offsetting effects must be expected. In fact, studies involving a known aromatase-inhibitor confirm such offsetting effects. In these studies, it has been shown that the known aromatase-inhibitor, .DELTA..sup.1 -testolactone(Teslac.RTM.), does inhibit the conversion of androgens to estrogens, thereby causing a fall in the serum estrogen level; however, at the same time, it causes a rise in the serum androgen level. (See, e.g., R. A. Vigersky and A. R. Glass, "Effects of .DELTA..sup.1 -Testolactone on the Pituitary-Testicular Axis In Oligospermic Men," J. Clin. Endocrin. and Metab., 52, 897-902 (1981); R. M. Barone, I. M. Shamonki, P. K. Siiteri, and H. L. Judd, "Inhibition of Peripheral Aromatization of Androstenedione to Estrone in Postmenopausal Women with Breast Cancer Using .DELTA..sup.1 -Testolactone," J. Clin. Endocrin. and Metab., 49, 672-676 (1979); S. P. Marynick, D. L. Loriaux, R. J. Sherins, J. C. Pita, Jr., and M. B. Lipsett, "Evidence That Testosterone Can Suppress Pituitary Gonadotropin Secretion Independently of Peripheral Aromatization," J. Clin. Endocrin. and Metab., 49, 396-398 (1979); and P. K. Siiteri and E. Aubrey Thompson, "Studies of Human Placental Aromatase," J. Ster. Biochem., 6, 317-332 [1975].) Thus, administration of an aromatase-inhibitor (e.g., also including the aromatase-inhibitors disclosed in U.S. Pat. No. 4,235,893), would be expected to have a beneficial effect on BPH in view of the fact that it would lower estrogen levels; however, in view of the fact that its administration would be expected to increase androgen levels, it would be expected to have a negative influence on BPH. Accordingly, the prior art contains no suggestion that administration of an aromatase-inhibitor could be effective in treating BPH. Their use in the prior art has been restricted to indications involving increased estrogen levels only, and not increased androgen levels. (U.S. Pat. No. 4,235,893.)
Moreover, because administration of aromatase-inhibitors leads to an increase in androgen levels, it also would not be expected that co-administration of an aromatase-inhibitor and an antiandrogen would produce effective prophylaxis and/or treatment of BPH. It would be a priori counterproductive to administer an agent which increases the level of antagonistic androgen and then co-administer an antiandrogen to alleviate that negative effect. There is no basis for predicting that such treatment, in fact, would not cause a worsening of the condition. It would, moreover, be expected that the amount of antiandrogen to be co-administered in this unfavorable method would be greatly increased in comparison to the amount necessary in its coadministration with an antiestrogen in accordance with the prior art.
Since the prostate gland of men possesses estrogen receptors and the interstice (stroma) is a target organ for estrogens in BPH, the estrogens bring about the stimulation of the fibromuscular tissue. From this it follows that, in humans, prostatic hyperplasia stimulated by estrogens is predominantly a disorder of the fibromuscular interstice (stroma).
These findings are also supported by investigations carried out on dogs. It has been possible to show that estrogen treatment leads to a stimulation of the glandular epithelium (parenchyma) (Tunn, U. W., Schuering, B., Senge, Th., Neumann, F., Schweikert, H. U. and H. P. Rohr (1981): "Morphometric analysis of prostates in castrated dogs after treatment with androstanediol, estradiol and cyproterone acetate," Invest. Urol. 18: 289-292.) These studies also clearly show that both estrogenic effects and androgenic effects are important in BPH. Also, in autoradiographic studies on human prostatic hyperplasia tissue, it has been possible to show that it is only the glandular epithelium (parenchyma) that is a target organ for androgens, and not the interstice.